Anti-Inflammatory and Antioxidant Effects of (6S,9R)-Vomifoliol from Gaultheria procumbens L.: In Vitro and Ex Vivo Study in Human Immune Cell Models

(6<i>S</i>,9<i>R</i>)-vomifoliol (VO) is a natural norisoprenoid of the megastigmane type derived from <i>Gaultheria procumbens</i>, an aromatic, evergreen shrub whose leaves, fruits, and aerial parts are used in traditional phytotherapy to treat oxidative stress and inflammation-related disorders. The plant is known as a rich source of essential oil and polyphenols. However, the levels of other constituents of <i>G. procumbens</i>, including VO, have yet to be explored. There is also a knowledge gap in the pharmacological potential of VO in the context of inflammation. Therefore, the present study aimed to investigate the accumulation of VO in leaves, stems, and fruits of <i>G. procumbens</i> and to determine its antioxidant and anti-inflammatory effects in non-cellular in vitro and cell-based models of human immune cells ex vivo. The GC-FID-MS (gas chromatography coupled with flame ionisation detector and mass spectrometer) analysis revealed the leaves as the richest source of VO (0.36 mg/g dw of the plant material) compared to other <i>G. procumbens</i> organs. In non-cellular activity tests, VO showed comparable to positive control anti-inflammatory activity against lipoxygenase, with significantly weaker impact on hyaluronidase and cyclooxygenase-2, and no effect on cyclooxygenase-1 isozyme. VO at 5-75 μM revealed a significant and dose-dependent ability to reduce the reactive oxygen species (ROS) level, downregulate the release of pro-inflammatory cytokines [tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), IL-6, and IL-1β] and tissue-remodelling enzymes (elastase-2, metalloproteinase-9), and up-regulate the secretion of anti-inflammatory cytokine IL-10 in bacterial lipopolysaccharide (LPS)- and <i>N</i>-formyl-L-methionyl-L-leucyl-L-phenylalanine (<i>f</i>MLP)-stimulated human neutrophils and peripheral blood mononuclear cells (PBMCs) ex vivo. Furthermore, a significant reduction in <i>IL-6</i>, lipoxygenase (<i>LOX</i>), nuclear factor κ-light-chain-enhancer of activated B cells 1 (<i>NF-κB1</i>), and <i>NF-κB2</i> gene expression in LPS-stimulated peripheral blood lymphocytes was demonstrated by real-time PCR. The cellular safety of VO at 5-75 μM was confirmed by flow cytometry, with the viability of neutrophils and PBMCs after incubation with VO at 93.8-98.4%. The results encourage further studies of VO as a promising non-cytotoxic natural anti-inflammatory agent and support the use of leaves of <i>G. procumbens</i> in the adjuvant treatment of oxidative stress and inflammation-related diseases of affluence.